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Biochem J
2001 Mar 15;354Pt 3:511-9. doi: 10.1042/0264-6021:3540511.
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Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter.
Goswami T
,
Bhattacharjee A
,
Babal P
,
Searle S
,
Moore E
,
Li M
,
Blackwell JM
.
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In mammals, natural-resistance-associated macrophage protein 1 (Nramp1) regulates macrophage activation and is associated with infectious and autoimmune diseases. Nramp2 is associated with anaemia. Both belong to a highly conserved eukaryote/prokaryote protein family. We used Xenopus oocytes to demonstrate that, like Nramp2, Nramp1 is a bivalent cation (Fe2+, Zn2+ and Mn2+) transporter. Strikingly, however, where Nramp2 is a symporter of H+ and metal ions, Nramp1 is a highly pH-dependent antiporter that fluxes metal ions in either direction against a proton gradient. At pH 9.0, oocytes injected with cRNA from wild-type murine Nramp1 with a glycine residue at position 169 (Nramp1(G169); P=3.22x10(-6)) and human NRAMP1 (P=3.87x10(-5)) showed significantly enhanced uptake of radiolabelled Zn2+ compared with water-injected controls. At pH 5.5, Nramp1(G169) (P=1.34x10(-13)) and NRAMP1 (P=1.09x10(-6)) oocytes showed significant efflux of Zn2+. Zn2+ transport was abolished when the proton gradient was dissipated using carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Using pre-acidified oocytes, currents of 130+/-57 nA were evoked by 100 microM Zn2+ at pH 7.5, and 139+/-47 nA by 100 microM Fe2+ at pH 7.0, in Nramp1(G169) oocytes; currents of 254+/-49 nA and 242+/-26 nA were evoked, respectively, in NRAMP1 oocytes. Steady-state currents evoked by increasing concentrations of Zn2+ were saturable, with apparent affinity constants of approx. 614 nM for Nramp1(G169) and approx. 562 nM for NRAMP1 oocytes, and a curvilinear voltage dependence of transporter activity (i.e. the data points approximate to a curve that approaches a linear asymptote). In the present study we propose a new model for metal ion homoeostasis in macrophages. Under normal physiological conditions, Nramp2, localized to early endosomal membranes, delivers extracellularly acquired bivalent cations into the cytosol. Nramp1, localized to late endosomal/lysosomal membranes, delivers bivalent cations from the cytosol into this acidic compartment where they may directly affect antimicrobial activity.
Aballay,
Zn2+ depletion blocks endosome fusion.
1995,
Pubmed
Abel,
Susceptibility to leprosy is linked to the human NRAMP1 gene.
1998,
Pubmed
Atkinson,
Ectopic expression of Nramp1 in COS-1 cells modulates iron accumulation.
1998,
Pubmed
Barton,
Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways.
1995,
Pubmed
Bellamy,
Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.
1998,
Pubmed
Blackwell,
Genetic regulation of macrophage activation: understanding the function of Nramp1 (=Ity/Lsh/Bcg).
1999,
Pubmed
Blackwell,
Understanding the multiple functions of Nramp1.
2000,
Pubmed
Brown,
Stabilized expression of mRNA is associated with mycobacterial resistance controlled by Nramp1.
1997,
Pubmed
Canonne-Hergaux,
Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron.
1999,
Pubmed
Cellier,
Resistance to intracellular infections: comparative genomic analysis of Nramp.
1996,
Pubmed
Fleming,
Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.
1997,
Pubmed
Fleming,
Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport.
1998,
Pubmed
Fritz,
Quantitative photometrical assessment of iron deposits in synovial membranes in different joint diseases.
1996,
Pubmed
Garner,
Endogenous ferritin protects cells with iron-laden lysosomes against oxidative stress.
1998,
Pubmed
Gerlach,
Altered brain metabolism of iron as a cause of neurodegenerative diseases?
1994,
Pubmed
Gomes,
Evidence for a link between iron metabolism and Nramp1 gene function in innate resistance against Mycobacterium avium.
1998,
Pubmed
Goswitz,
Structural features of the uniporter/symporter/antiporter superfamily.
1995,
Pubmed
Griffith,
Membrane transport proteins: implications of sequence comparisons.
1992,
Pubmed
Gruenheid,
The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes.
1999,
Pubmed
Gruenheid,
Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome.
1997,
Pubmed
Gunshin,
Cloning and characterization of a mammalian proton-coupled metal-ion transporter.
1997,
Pubmed
,
Xenbase
Hackam,
Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification.
1998,
Pubmed
Hirsch,
Iron metabolism and Parkinson's disease.
1998,
Pubmed
Hofmeister,
The natural resistance-associated macrophage protein gene is associated with Crohn's disease.
1997,
Pubmed
Hughes,
Protein phylogenies provide evidence of a radical discontinuity between arthropod and vertebrate immune systems.
1998,
Pubmed
Jabado,
Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane.
2000,
Pubmed
Jellinger,
Iron and ferritin in substantia nigra in Parkinson's disease.
1993,
Pubmed
Krantz,
Pathogenesis and treatment of the anemia of chronic disease.
1994,
Pubmed
Kuhn,
Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169.
1999,
Pubmed
Lang,
Nramp1 transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on antigen processing and presentation.
1997,
Pubmed
Lee,
The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms.
1998,
Pubmed
Liu,
Post-translation control of Nramp metal transport in yeast. Role of metal ions and the BSD2 gene.
1999,
Pubmed
Liu,
Mutational analysis of Saccharomyces cerevisiae Smf1p, a member of the Nramp family of metal transporters.
1999,
Pubmed
Marger,
A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport.
1993,
Pubmed
Multhaup,
Amyloid precursor protein, copper and Alzheimer's disease.
1997,
Pubmed
Nelson,
Metal ion transporters and homeostasis.
1999,
Pubmed
Nelson,
Energizing porters by proton-motive force.
1994,
Pubmed
Orgad,
Metal ions suppress the abnormal taste behavior of the Drosophila mutant malvolio.
1998,
Pubmed
Picard,
Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool.
2000,
Pubmed
Pinner,
Functional complementation of the yeast divalent cation transporter family SMF by NRAMP2, a member of the mammalian natural resistance-associated macrophage protein family.
1997,
Pubmed
Rodrigues,
malvolio, the Drosophila homologue of mouse NRAMP-1 (Bcg), is expressed in macrophages and in the nervous system and is required for normal taste behaviour.
1995,
Pubmed
Sanjeevi,
Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis.
2000,
Pubmed
Searle,
Localisation of Nramp1 in macrophages: modulation with activation and infection.
1998,
Pubmed
Shaw,
Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35.
1996,
Pubmed
Supek,
A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria.
1996,
Pubmed
Varela,
Nucleotide and deduced protein sequences of the class D tetracycline resistance determinant: relationship to other antimicrobial transport proteins.
1993,
Pubmed
Vidal,
Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg.
1993,
Pubmed
Wall,
Isolation of plasma membrane complexes from Xenopus oocytes.
1989,
Pubmed
,
Xenbase
Yip,
The roles of inflammation and iron deficiency as causes of anemia.
1988,
Pubmed
Yuan,
Effects of iron- and hemoglobin-loaded human monocyte-derived macrophages on oxidation and uptake of LDL.
1995,
Pubmed
Yuan,
Iron in human atheroma and LDL oxidation by macrophages following erythrophagocytosis.
1996,
Pubmed
Zwilling,
Role of iron in Nramp1-mediated inhibition of mycobacterial growth.
1999,
Pubmed
de Chastellier,
Implication of phagosome-lysosome fusion in restriction of Mycobacterium avium growth in bone marrow macrophages from genetically resistant mice.
1993,
Pubmed
